BMS/AZ's SAVOR and Takeda's EXAMINE cardiovascular outcome trials show non-inferior results at European Society of Cardiology, reinforcing CV safety; reassuring results on pancreatitis and pancreatic cancer ~ Interview with Prof. Itamar Raz on SAVOR - September 2, 2013

We are at the European Society of Cardiology in Amsterdam, where the results have just been presented for SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), BMS/AZ’s study of Onglyza (saxagliptin) and EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial for Takeda’s Nesina (alogliptin) during an ESC Hot Line session – these sessions are among the busiest at the conference due to the late-breaking nature of each of the presentations. In this document, we bring you early highlights of the results of both studies, based on the in-depth presentations that just took place, as well as highlights of our interview with Professor Itamar Raz, one of SAVOR’s principal investigators. Professor Raz expounds on potential reasons why it was expected that DPP-4 inhibitors might show CV superiority, reasons why SAVOR turned out neutral, why the trial was designed with such a short follow-up, and the importance of glycemic control beyond solely cardiovascular risk reduction.

Quite reassuringly, neither cardiovascular outcome trial found an imbalance in pancreatitis or pancreatic cancer, with EXAMINE actually reporting zero instances of pancreatic cancer. As a reminder, the 16,000+ patient SAVOR study was conducted at more than 700 sites worldwide and the EXAMINE study was significantly smaller, at around 5,400 patients, conducted at just under 900 sites in the US, Europe, and Asia. Both were randomized, double-blind, placebo-controlled trials designed to fulfill post-marketing requirements for the US Food and Drug Administration on cardiovascular safety in patients with type 2 diabetes at risk for cardiovascular disease. Both trials had secondary objectives of investigating cardiovascular superiority if the safety (non-inferiority) primary objective was met. Both trials had quite short median follow up periods – EXAMINE’s was 18 months, while SAVOR’s was 2.1 years – and we believe the length of the trials will be a widely discussed element, namely what longer trials may have shown. Both trials demonstrated cardiovascular non-inferiority compared to placebo, and neither demonstrated cardiovascular superiority; we believe following the presentations that observers will continue to reinforce how DPP-4 inhibitors can reduce microvascular complications through safely reducing blood glucose levels. Rather notably, SAVOR presenter and principal investigator Dr. Deepak Bhatt (Brigham and Women’s Hospital, Newton, MA) stated quite confidently here in Amsterdam today that he would be comfortable extrapolating the results of both of these trials to the class of DPP-4 inhibitors as a whole. We remain curious whether BI/Lilly’s CAROLINA trial for Tradjenta (linagliptin), which compares Tradjenta to a sulfonylurea, will show superiority compared to a sulfonylurea. All in all, given the time period of trials and pancreatitis/pancreatic cancer results, we think the day was a win for BMA/AZ and Takeda. While cardiologists don’t walk away with an “extra” reason to use DPP-4 inhibitors, some major questions have been addressed (to the extent the relatively short trials show), and there is now more evidence from our view that reinforces safety of DPP-4 inhibitors.

Highlights for Takeda’s EXAMINE (Nesina)

The primary endpoint of MACE (CV death, myocardial infarction, and stroke) occurred at a similar rate in alogliptin and placebo-treated patients (11.3% vs. 11.8%, respectively; P<0.001 for non-inferiority; HR=0.96 with the upper bound of the one-sided repeated confidence interval at 1.16). The secondary endpoint of MACE+ (the primary outcome plus urgent revascularization due to unstable angina) was also similar between treatment groups (HR=0.95 with the upper bound of the one-sided repeated confidence interval at 1.14). The HR for cardiovascular death was 0.85 (upper bound of 95% CI: 1.10), and the HR for all-cause mortality was 0.88 (upper bound of 95% CI: 1.08). Notably, there were no reported cases of pancreatic cancer during the trial and additionally, the rates of acute and chronic pancreatitis were “low and similar” in each treatment group. The mean follow up in EXAMINE was 18 months, and the maximum follow up was 40 months (n=5,380).

Highlights for BMS/AZ’s SAVOR-TIMI 53 (Onglyza)

The HR for the primary outcome of MACE was exactly 1.00 (95% CI: 0.89-1.12; p<0.001 for non-inferiority; p=0.99 for superiority), and the HR for the secondary endpoint of MACE+ (MACE plus hospitalization for heart failure, unstable angina, or coronary revascularization) was 1.02 (95% CI: 0.94-1.11). There was an unexpectedly greater risk of hospitalization due to heart failure in the Onglyza group than the placebo group: HR=1.27 (95% CI: 1.07-1.51; p=0.007), though in the group that exhibited excess heart failure risk, there was no increased risk of all-cause mortality, CV mortality, occurrence of the primary endpoint, or occurrence of the secondary endpoint. The rate of pancreatitis (including both acute and chronic) was identical between Onglyza and placebo groups at 0.3%. There was a trend towards reduced pancreatic cancer in the Onglyza group with p=0.095. The press release states that the rate of "renal abnormalities" was higher in the Onglyza group (5.8% vs. 5.1%; p=0.04), although it also states that Onglyza also reduced and prevented progression of microalbuminuria. The median follow up for this 16,492-person trial was 2.1 years, and maximum was 2.9 years.

• Notably, presenters were questioned before and after the session on whether there was any compelling reason to take DPP-4 inhibitors at all if there is no cardiovascular benefit. SAVOR presenter and principal investigator Dr. Deepak Bhatt (Brigham and Women’s Hospital, Newton, MA) remarked on the discrepancy between endocrinologists’ and cardiologists’ responses to the results – he noted that while endocrinologists largely saw the results as “terrific” while cardiologists worried about the lack of cardiovascular benefit and increased risk of heart failure. This was interesting from our view, since the reason the trials were required by the FDA was to assess whether there is reduced safety associated with DPP-4 inhibitors. As Dr. Raz discusses in the interview below, although there was increased hospitalization for heart failure, there was no increase in cardiovascular death, in all-cause mortality, or in either the primary or secondary composite endpoints, suggesting additional risk is modest – he actually believes the increased hospitalization was due to doctors’ increased concern about being sued by patients in the US for not sending the patients to the hospital! Dr. Bhatt emphasized that improved glycemic control, while its relationship with macrovascular complications is not crystal clear, is strongly correlated with improved risk for microvascular complications.

In-Depth Interview with Professor Itamar Raz

We had the privilege to discuss SAVOR-TIMI 53 results with one of the principal investigators, Professor Itamar Raz. Professor Raz holds an MD from Hadassah Medical School at the Hebrew University of Jerusalem where he is a professor of Internal Medicine and the Head of the Diabetes Unit at Hadassah University Hospital. Professor Raz is the head of the Israel National Council of Diabetes, which is responsible for formulating national policies. In addition, Professor Raz is President of D-Cure, a non-profit organization that promotes and funds scientific research in Israel for finding a cure and better treatments for diabetes. At Hadassah, Professor Raz is involved in basic research (focusing on the beta cell in diabetes) and clinical research and is currently leading several large international CV and renal outcome diabetes studies as well as studies related to prevention of type 1 diabetes. He has over 260 publications to his credit in professional peer-reviewed journals including a biennial publication of a Supplement to Diabetes Care summarizing proceedings of the European Controversies to Consensus in Obesity, Diabetes and Hypertension (CODHy) meeting. In addition he serves on several editorial boards of leading medical journals.

Jessica Dong: Dr. Raz, thank you so much for meeting with me here at ESC. The point estimate of 1.0 is perhaps higher than we would have expected from previous pooled analyses of DPP-4 inhibitor data showing that the point estimate was <1.0. What might be the discrepancy?

Dr. Raz: The question is whether meta-analyses give you the right answer. It is surprising, in a way, that in spite of the fact that DPP-4 inhibitors had a rationale of reducing cardiovascular events, and in spite of the fact that in all the different phase 2 and phase 3 trials, there was a trend toward reduction (with a hazard ratio between 0.5-0.7 in most), still, at the end of the day the hazard ratio in SAVOR was 1.0.

Several things come to mind:

• We did a very good study [in terms of patients’ existing cardiovascular protection]. Nearly 90% of patients at end of study were treated with statins. The study started with 78% of patients on statins and we raised it to nearly 90%.

• No drug up until now has shown cardiovascular disease reduction beyond statins. The JUPITER study demonstrated that cardiovascular outcomes are mainly related to LDL; even with very low HDL, if LDL is low, cardiovascular disease will be prevented. So it may have been because we treated so well with statins, and controlled other cardiovascular risk factors like cholesterol, blood pressure, aspirin therapy, etc, the chance to show benefit was very low.

• Another explanation might be related to what we saw in ORIGIN – on the one hand, the drug may be improving risk of cardiovascular events, but some other thing that happened e.g., hypoglycemia or any other thing related to the therapy that was not necessarily related to the drug may have prevented us from seeing the benefit.

Jessica Dong: Is there any explanation for why heart failure was higher in Onglyza? Has this been observed in previous trials?

Dr. Raz: There was increased hospitalization for heart failure. There is a difference between hospitalization for heart failure and heart failure. Many times you tend to hospitalize your patients when – although in this trial all cases were adjudicated – many times, for example, in the US where physicians want to make sure that patients will never sue them, they are very quick to send patients for hospitalizations. There was an increase in hospitalization for heart failure. What is the reason? If you look at animal studies, DPP-4 inhibitors, if anything, should prevent heart failure. The reason is there are several proteins that are important or at least we think are important for prevention of important. One is BNP. This is a very important protein that increases in patients with heart failure and we think it’s increased because it’s supposed to protect patients from heart failure. Several animal studies supported this, but a very large human study couldn’t show that when you infuse BNP you improve outcomes. DPP-4 inhibitors prevent degradation of BNP.

DPP-4 inhibitors also prevent degradation of other proteins e.g., SDF1 (stromal derived factor 1) – a very important protein. This is a protein that causes stem cells in the bone marrow to develop into endothelial cells. Whenever you have problems with vessel repair, this is increased and causes vessel repair. This is a very important protein to prevent atherosclerosis and a very important protein to prevent heart failure. It has been demonstrated in animal models that SDF1 can improve or reduce heart failure in animal models. DPP-4 inhibtors prevent degradation of SDF1 and we know diabetic patients tend to have lower SDF1. So we expect that increasing SDF1 in diabetic patients would prevent heart failure.

Is this heart failure a true finding? Sometimes in such a large study, and the difference would be 60 patients – the result can still be by chance. We do think it’s a true finding, because it was a pre-specified adjudicated endpoint.

Jessica Dong: Was there a specific patient population at higher risk for heart failure?

Dr. Raz: We did find that there was a large group of patients who were at very low risk for hospitalization for heart failure – so we could identify very easily a relatively small group who were at higher risk. I wouldn’t say, however, we should not suggest the drug for medium- and high-risk patients. We should be careful for high-risk patients when we see two, three, four times more risk – then we should be careful. But you have to remember this is a very good drug – we only talk about negative things. We have to remember that all the other side effects suspected of this group of drugs like pancreatitis, pancreatic cancer, and fractures, liver abnormalities, lymphocytes – all these things were found to be similar to placebo, so no higher risk.

When looking at patients with heart failure and looking at how many patients when they developed heart failure stopped the drug – you see that in the placebo group, 50-60% stopped the drug. However, in the saxagliptin group, only 20% stopped, which means maybe the quality of life under this drug was much better. This is one thing we are going to check. We know patients who used the drug and patients treated with insulin, we saw, on the one hand, improvements in A1c in spite of relative reduction in insulin dose versus placebo. Along with the A1c reduction with Onglyza, there was not an increase in hypoglycemia. 

It’s very simple – saxagliptin doesn’t cause weight gain, it has cardiovascular safety, can be used to improve blood glucose control, patients can reduce the amount of insulin without increasing risk of hypoglycemia and at the same time it seems also to prevent microvascular disease, which is the main issue beyond CVD. This is a very good drug. It was the same thing with ACCORD, ADVANCE, and VADT –people were asking if we don’t improve cardiovascular outcomes and cardiovascular disease is still the main reason for morbidity and mortality in diabetes patients, why should we put so much effort?

The answer is very simple – in the US, the number of people on dialysis only grows with time. The reason is that we try to stop nephrology at a late stage. We have had some success – we have reduced nephropathy by 35% – but at the same time, we have doubled the number of diabetes patients, so at end of the day, more people are losing eyesight, going on dialysis, and having amputations, so we have to do our best to bring people to their target A1c.

In order to do that, we need more than metformin. Each one of the other drugs has an efficacy that is quite similar, but has its own side effects and safety issues. Weight gain, hypoglycemia, and other deleterious effects. Each drug has its own limitations. We need those drugs and we need to know to whom to give it and when to give it. 

Jessica Dong: Is two years enough to see results?

Dr. Raz: Most of time if you want to see an effect you have to follow for at least five to seven years. If you follow two to three years you won’t see anything. So you can ask then why did you expect to have superiority?

If you look at phase 2-3 studies of saxagliptin you can see that adding drug to patient there was change in cardiovascular outcomes that started several weeks after drug was given. This was in one to two months. We thought that it might be the DPP-4 inhibitor had both and acute and long-term effects like you sometimes see with statins. We hoped that through the acute effect we would see the result – otherwise if you really wanted to see result you would have to follow patients for more than four to five to six years.

Would something happen if we kept patients in the trial for that long? We have no answer. We cannot say.  It might be. For example, if you look at the ADVANCE study, it showed the same thing, like SAVOR after 2 years there was one line over the other. After four years the lines started to spread away. Was this by chance, and would they ultimately converge? We don’t know but the ADVANCE study was a good example that in a five-year study, you could see that something might start to happen after four years. If you look at one for two to three years, you see nothing.

Jessica Dong: Would you discuss the mechanism for the theorized acute cardiovascular effect with DPP-4 inhibitors?

Dr. Raz: DPP-4 inhibitors increase several proteins that can change the course of the disease in diabetic patients. One is GLP-1. DPP-4 inhibitors increase the physiologic levels of GLP-1 by two to three times. GLP-1 has been shown to take an important role in the myocyte response to stress. Glucose metabolism improves in myocytes with GLP-1. You can show that with apoptotic proteins that cause accelerated death or anti-apoptotic proteins that prevent accelerated death. When you give GLP-1 or DPP-4 inhibitors, there is an increase in anti-apoptotic cells and a decrease in apoptotic cells. So it might be that GLP-1 prevents occurrence of acute myocardial infarction even if you have something like unstable angina or induction in heart perfusion and so on. In animal models, treatment with DPP-4 inhibitors will reduce size of myocardial infarctions. So all together, you can assume that patients who are at very high risk of developing acute myocardial infarction might be protected by DPP-4 inhibitors. 

Another mechanism – DPP-4 inhibitors prevent atherosclerosis as shown in animal models. DPP-4 inhibitors stabilizes plaque by increasing the fibrosis of the plaque and decreasing inflammation in plaque. We know how important this could be; when a plaque becomes fibrotic or when the inflammation goes down, the chance the plaque will break becomes much lower. These hypotheses, to my mind, need much longer study and examination of more than just the acute effect. So I think the different mechanisms that have been shown for why DPP-4 inhibitors might prevent myocardial infarction may need more time.

Jessica Dong: Will there be a longer-term follow up for SAVOR?

Dr. Raz: No. It would be too complicated.

Jessica Dong: The 0.5% (0.3% placebo-adjusted) A1C reduction seemed quite modest. Do you have any thoughts on this?

Dr. Raz: When you add a DPP-4 like saxagliptin to metformin or add to SFU, and the baseline A1C is above 8%, you do see, most of the time, a reduction of 0.6-0.7%, but when you add to insulin, even with patients with A1Cs of 8.5% or 9%, there is a smaller effect. Most of time, it’s around a 0.4-0.5% drop.

Forty percent of these patients were treated with insulin. On the other hand, there were patients who were enrolled with very low A1C below 6.5% - around 10% of patients. (You saw something similar with ORIGIN; in ORIGIN, when insulin was added, the A1C fell by only 0.3-0.4% because these patients had such low baseline A1cs.) When you combine these two factors, the mean A1C reduction was modest.

Jessica Dong: What was the baseline A1C and diabetes duration for the treatment and placebo groups?

Dr. Raz: It was nearly 8%, approximately 8%. The average diabetes duration was 10 years.

Jessica Dong: Can you characterize how severe the CVD was for the inclusion criteria?

Dr. Raz: The patients had history of acute MI, and if there was no history, they had to have double vessel disease with more than 50% obstruction. So these patients had clear-cut cardiovascular disease. Many had more than one MI in the past. The mean diabetes duration, as I noted, was more than 10 years. 21% of the patients were patients with multiple risk factors without a history of cardiovascular disease. These patients had to be at the age of 55 or more for men, 60 or more for women and had to have at least one more cardiovascular risk factor like hypertension, dyslipidemia, and smoking. These patients were high risk to develop cardiovascular disease if they didn’t have cardiovascular disease already.

Jessica Dong: That’s interesting - if it had been studied in a lower-risk population, do you think we would have seen a different result?

Dr. Raz: There is no clear-cut answer. UKPDS showed that there is such a thing as a legacy effect. When you reduce glucose levels with insulin, SFUs, or metformin, you will reduce cardiovascular events over a long time. But UKPDS was in newly diagnosed patients. In studies like ADVANCE, ACCORD, VADT, studies with long disease duration similar to SAVOR, which was between 8 and 11 years, more and more data show when you try to change course of disease after 10 years, your chances are very low. More and more, we learn that when you treat early, there is a good chance that you see results. There is now a new study in NEJM, Look AHEAD¹– if you look at that study, nearly 10 years of intensive lifestyle that reduced blood pressure, A1C, weight, triglycerides, everything except LDL cholesterol, didn’t result in any change in CV outcomes and this after 10 years of follow up! And our study only showed two years. The question is why Look AHEAD didn’t show any change. If you look at Look AHEAD, the patients who didn’t have cardiovascular disease seemed to do better with intensified management. The hazard ratio was 0.86. Patients who had cardiovascular disease seemed to do worse with a hazard ratio of 1.13. When you try to change something too late, sometimes you might cause more deleterious effect than beneficial effect as was shown in ACCORD and VADT - VADT also showed perhaps increased mortality.

Jessica Dong: It certainly isn’t straightforward – and then, of course, if you try to intervene from the very start, this could take even longer to show an impact. Can you provide the pancreatitis event rate in X events per Y,000 patient-years?

Dr. Raz: I prefer not to talk about it until after the presentation. (Editor’s note – our interview took place just before the results were announced.)

Jessica Dong: Can you discuss renal abnormalities seen in the study?

Dr. Raz: The patients treated with Onglyza demonstrated a beneficial kidney effect. There was a reduced number of patients going from normoalbuminuria to microalbuminuria. And then reduced microalbuminuria to macroalbuminuria. The significance was very high at p=0.0001. Looking at creatinine, there was no difference. The short term could not show improvements in this kidney function test, but most of the time, two years is not enough to show a difference creatinine.

Jessica Dong: Did any sub-groups of individuals have significantly better or worse CV outcomes than the mean? In particular, we have heard that DPP-4 inhibitors may be more efficacious in Asian populations – were there any differences in outcomes or trends based on ethnic background?

Dr. Raz: All the groups responded the same in general with regard to cardiovascular outcomes – they were similar for all groups. Drug-naïve patients, those on monotherapy, insulin, and SFUs. All ethnicities, all patients – all of them had the same cardiovascular outcomes, which correlates to a primary endpoint hazard ratio of around 1.0.

Jessica Dong: How do you think incorporating these CVOT results into Onglyza’s and Nesina’s labels, respectively, affect patient and prescriber perception of safety?

Dr. Raz: No comment.

Jessica Dong: Thinking bigger picture, will the FDA Advisory Committee ruling on Avandia change how the FDA views and values results of cardiovascular outcomes trials? Since questions over Avandia’s cardiovascular safety were a precipitating factor in the development of the FDA’s 2008 Cardiovascular Guidance, will the FDA’s more relaxed view on Avandia’s cardiovascular safety affect cardiovascular requirements for type 2 diabetes drugs moving forwards?

Dr. Raz: You can learn a lot from Avandia. One, you learn that meta-analysis must be very careful. From the beginning, I didn’t see any reason to keep Avandia off the market because of the meta-analyses. You can also learn that drugs like PPAR gamma are very good drugs. They are very effective; they protect the beta cell. But on other hand, it has deleterious effects, such as fractures in women. Pioglitazone (Takeda’s Actos) still has a question on cancer, and there is weight gain, fluid retention, etc., and in spite of this, it’s a very good drug if you know all these things and if you see any signs, you stop the drug.  No drug today doesn’t have any side effects, except maybe except metformin.

Jessica Dong: Thank you so much, Dr. Raz, for helping us with better understanding the results of SAVOR. We know all our readers will benefit from your early comments on this important study.

-- by Jessica Dong and Kelly Close